Project Summary The project seeks to improve the efficacy of blood transfusions (BTs), and thereby reduce the use of blood in BTs, by counteracting the increase in blood flow resistance caused by adding red blood cells (RBCs) to the circulation which increases blood viscosity thereby reducing oxygen delivery (DO2). Feasibility has been established from preliminary studies and BT studies, that show increased blood viscosity increases shear stress on the vascular endothelium which in turn causes vasodilation by stimulating the production of nitric oxide (NO). Our analytical studies of limited existing clinical BT data, and our more extensive studies on experimental animal models, show that beneficial effects due to BTs can be significantly improved by increased blood flow causing an increase of DO2 which is proportional to the product cardiac output (CO) times oxygen carrying capacity (CaO2): DO2 = CO x CaO2. Our studies also show that flow increases during BTs are due to vasodilation related to increased bioavailability of circulating NO. Most significantly, an analysis of existing clinical data indicates that O2 delivery by BTs falls short of being directly proportional to the increase of hematocrit (Hct), revealing that as much as 1/3 of the transfused RBCs do not contribute to increasing O2 delivery. We propose to circumvent the hindrance to blood flow due to increased blood viscosity by BTs by increasing blood flow via NO mediated vasodilation by three different approaches: 1) Increasing plasma viscosity after BT by means of the viscogenic starch-based plasma expander Hextend, approved for clinical use but not for treating anemia. Our macro and microvascular experimental studies show that this is a highly effective approach for increasing flow that could become clinically applicable in the very short term; 2) Intravenous introduction of well tested biocompatible NO carrying and releasing silane nanoparticles (NO-nps) with tunable NO type (NO, SNO, nitrite) and rates of release, particularly suitable for the immediate treatment of anemia in conditions of endothelial dysfunction that limit bioavailability; and, 3) A pharmacological approach where existing NO based vasodilators, already approved for use for other treatments are re-purposed for increasing flow in anemia via either intravenous nanoparticle or oral administration. We propose validating our hypothesis by: 1) Analyzing in vivo microvascular effects of replacing O2 delivery by increased flow vs. increased CaO2; 2) Determining whether an NO based support of BTs improves treating anemia by limiting the amount of needed transfused blood, and, 3) Determining the relative efficacy of oral versus intravenous NO enhancement strategies. A positive outcome for this project will make the treatment of acute anemia less costly, more effective, more practical, and safer.